Modeling the role of dose for infection and vaccination outcomes

Slides: https://www.andreashandel.com/presentations/

Andreas Handel

2025-03-26

Overview

  • Part 1 - Role of dose for infections
  • Part 2 - Role of dose for vaccines

Part 1 - Dose and Infections

Background

  • For infections, exposure to a higher pathogen dose is generally associated with an increased risk of infection (e.g., ID50, Quantitative Microbial Risk Assessment).

Influenza infection in humans

Teunis et al. 2010 Epidemics

Norovirus infection in humans

Teunis et al. 2020 Epidemics

Pasteuria ramosa infections of Daphnia magna

Ben-Ami, Ebert, Regoes. 2010 Am Nat

Mostly open questions

  • If infection occurs what is the impact of dose on outcomes?
    • Pathogen kinetics and shedding/transmissibility
    • Symptoms/disease severity
    • Immune response, protective immunity
  • What mechanisms of interactions between pathogen and host produce observed outcomes?

Viral kinetics

Virus kinetics for different viral infections.

Li & Handel 2014 JTB

Viral kinetics

Viral kinetics modeling

\[ \begin{aligned} \textrm{Uninfected cells} \qquad \dot{U} & = - bUV \\ \textrm{Infected cells} \qquad \dot{I} & = bUV - d_I I - k_M M I - k_T T I\\ \textrm{Virus} \qquad \dot{V} & = pI - d_V V \\ \textrm{Macrophages} \qquad \dot{F} & = (s + g_V)(M^* - M - \alpha k_M M I) - d_M M \\ \textrm{T cells} \qquad \dot{T} & = \frac{r_T T V}{V + h_V} - d_T T \\ \end{aligned} \]

Viral kinetics modeling

Virus load after norovirus infection

Ge et al 2023 EID

Virus load after norovirus infection

Dose dependence of virus kinetics

Impact of dose on symptoms following norovirus infection

Impact of dose on antibodies following norovirus infection

Part 1 Summary

  • Given infection, dose influences virus kinetics in some instances (e.g. ADV, IBV) and has little impact in other instances (e.g., norovirus).
  • Dose seems to have a minor impact on symptoms and antibody response for norovirus.
  • We need to further study the mechanisms by which dose impacts outcomes.

Part 2 - Vaccines

Current approaches to dose choice

  • A few doses are explored in phase I/II trials, one is chosen for phase III and licensure.

Example of BioNTech/Pfizer COVID Vaccine

Live influenza vaccine kinetics

Handel et al 2018 PLoS Comp Bio

Model prediction for live vaccine

Inactivated influenza vaccine kinetics

Model prediction for inactivated vaccine

SD versus HD Influenza Vaccines

  • HD vaccine protects better against the strains contained in the vaccine
  • Does HD also induce a better protective antibody response against other influenza strains?

SD versus HD vaccine study

Billings et al 2025 JID

Antibodies after HD/SD vaccine

Antibody kinetics following norovirus vaccination

Antibody kinetics following norovirus vaccination

Part 2 Summary

  • Dose seems to have an impact for broad induction of antibodies following influenza vaccination
  • Dose seems to have inconsistent effects antibodies following norovirus vaccination
  • Modeling dose could head to better prediction of optimal dose

Acknowledgements

  • Students: Zane Billings, Murphy John, Yang Ge
  • Other collaborators: Many
  • Data: Ted Ross, Ben Lopman, Takeda
  • Funding: NIH